A1 Refereed original research article in a scientific journal
The Mechanism of Cleavage and Isomerisation of RNA Promoted by an Efficient Dinuclear Zn2+ Complex
Authors: Korhonen H, Mikkola S, Williams NH
Publisher: WILEY-V C H VERLAG GMBH
Publication year: 2012
Journal: Chemistry - A European Journal
Journal name in source: CHEMISTRY-A EUROPEAN JOURNAL
Journal acronym: CHEM-EUR J
Number in series: 2
Volume: 18
Issue: 2
First page : 659
Last page: 670
Number of pages: 12
ISSN: 0947-6539
DOI: https://doi.org/10.1002/chem.201100721
Abstract
The cleavage and isomerisation of uridine 3'-alkylphosphates was studied in the presence of a dinuclear Zn2+complex, 3. The rate acceleration of the cleavage by 1 mM 3 is approximately 106-fold under neutral conditions. Most remarkably, the complex also promotes the isomerisation of phosphodiester bonds, although the rate-enhancement is more modest: under neutral conditions complex 3 (1 mM) catalyses isomerisation by about 500-fold. The observation of this reaction shows that the reactions of these substrates catalysed by 3 proceed through a stepwise mechanism involving an intermediate phosphorane. A beta lg value of -0.92 was determined for the 3-promoted cleavage reaction, and modest kinetic solvent deuterium isotope effects ranging from 1.5 to 2.8 were observed. Isomerisation was less sensitive to the nature of the esterifying group, with a beta value of -0.5, and the kinetic solvent deuterium isotope effects were less than 1.5. Most of these characteristics of the 3-promoted cleavage are very similar to those for the cleavage of nucleoside 3'-phosphotriesters. These data are explained by a mechanism in which the complex primarily acts as an electrophilic catalyst neutralising the charge on the phosphate and stabilising an intermediate phosphorane, with general acid catalysis promoting the cleavage reaction. In contrast to the behaviour of triesters, isomerisation is significantly slower than cleavage; this suggests that the changes in geometry that occur during isomerisation lead to a much less stable complex between 3 and the phosphorane intermediate.
The cleavage and isomerisation of uridine 3'-alkylphosphates was studied in the presence of a dinuclear Zn2+complex, 3. The rate acceleration of the cleavage by 1 mM 3 is approximately 106-fold under neutral conditions. Most remarkably, the complex also promotes the isomerisation of phosphodiester bonds, although the rate-enhancement is more modest: under neutral conditions complex 3 (1 mM) catalyses isomerisation by about 500-fold. The observation of this reaction shows that the reactions of these substrates catalysed by 3 proceed through a stepwise mechanism involving an intermediate phosphorane. A beta lg value of -0.92 was determined for the 3-promoted cleavage reaction, and modest kinetic solvent deuterium isotope effects ranging from 1.5 to 2.8 were observed. Isomerisation was less sensitive to the nature of the esterifying group, with a beta value of -0.5, and the kinetic solvent deuterium isotope effects were less than 1.5. Most of these characteristics of the 3-promoted cleavage are very similar to those for the cleavage of nucleoside 3'-phosphotriesters. These data are explained by a mechanism in which the complex primarily acts as an electrophilic catalyst neutralising the charge on the phosphate and stabilising an intermediate phosphorane, with general acid catalysis promoting the cleavage reaction. In contrast to the behaviour of triesters, isomerisation is significantly slower than cleavage; this suggests that the changes in geometry that occur during isomerisation lead to a much less stable complex between 3 and the phosphorane intermediate.
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